Octreotide is commercially available under the brand name Sandostatin™ as a preserved solution filled in sterile 5 ml multidose vials in two strengths, 200 μg/ml and 1000 μg/ml. The present inventors had previously developed a multiple dose pen injection device containing solution of octreotide acetate that allowed self-administration of octreotide dose to the patients, as disclosed in the US Pat. Appl. Publ. No. 20140213984A1. During this time, the present inventors worked towards the development of an injection device, such as a pen injection device, having multiple doses that supply daily doses of octreotide for about a month or so. In particular, attempts were made to develop a solution of octreotide that had 5 times higher concentration, i.e. 5 mg/ml compared to the vial product Sandostatin™, so that the volume of injection is reduced five times. Advantageously, since the concentration of octreotide was increased five times, the volume required to deliver equivalent dose was lowered five times, and correspondingly, the amount of preservative injected was reduced five times.
Typically it is known that peptide drugs, after oral or parenteral administration, show a poor bioavailability in the blood, e.g. due to their short biological half-lives in turn caused by their metabolic instability (see the disclosure in U.S. Pat. No. 5,538,739). The present inventors have faced the same problem of poor bioavailability for octreotide, as disclosed in the prior art.
An aqueous solution of octreotide acetate at a concentration equivalent to 5 mg/ml of octreotide base (as disclosed in example 1 of US 20140213984A1) filled in a pen injection device was injected subcutaneously in 20 microliters volume to human volunteers. The relative bioavailability of the octreotide acetate was determined and was compared with a Sandostatin™ solution that has 1 mg/ml octreotide acetate concentration, prepared in a volume of 100 microliters and injected through a conventional syringe. Surprisingly, the test sample of octreotide acetate provided only a 5% relative bioavailability, as compared to the Sandostatin™ solution.
Thus, it is an object of the present invention to solve the technical problem of poor bioavailability of octreotide in a salt form.
The present inventors have discovered a specific concentration range of 2.0 to 2.5 mg of octreotide base per ml of the solution, which unexpectedly provided satisfactory bioavailability equivalent to the Sandostatin™ 1 mg/ml solution at the same dosage.